CURRENT RESEARCH:

I am a developmental and molecular biologist interested in understanding the molecular mechanisms underlying normal development of the vertebrate embryo. The major goal of my research is to provide a clearer understanding of the molecular and morphological events involved in formation of the left-right axis, from transcriptional events in the nucleus to changes in cell-cell interactions. Proper formation of this axis is essential to direct subsequent asymmetric development and positioning of the internal organs, which permits their efficient packing within the body cavity. The organization of the internal organs is evolutionarily conserved in vertebrates: variations from the normal pattern disrupt physiological functioning and usually lead to life threatening complications.

The goal of the research in my lab is to identify molecules that participate in formation of the left-right axis and to define the mechanisms through which they effect asymmetric morphogenesis. As with all patterning events, asymmetric morphogenesis requires the conversion of extracellular signals into changes in intracellular gene expression that lead to cell/tissue remodeling, migration and differentiation. Although several molecules have been placed into a left-right signalling cascade, many are still unknown, and precisely how they direct the morphogenetic mechanisms remains obscure. In my laboratory, we are undertaking two approaches to improve our understanding of this process.

First, we are studying the homeodomain transcription factor, Pitx2c. We showed that Pitx2c has an evolutionarily conserved role in patterning the left-right axis and that it is the most downstream component of the pathway that directs asymmetric organ development. Pitx2c is asymmetrically expressed on the left side of tissues that are important for directing asymmetric morphogenesis, and in organs that become asymmetrically positioned with respect to the midline. Despite the fact that Pitx2c is a transcription factor, no gene targets have been identified with respect to left-right patterning. Currently, in my laboratory, we are characterizing the molecular mechanism(s) employed by Pitx2c to exert its developmental effects. Our future goals include the identification of Pitx2c transcriptional targets specific to left-right patterning.

Our second approach has been to identify new molecules involved in forming the left-right axis. To do this, we performed a subtractive screen for factors that are differentially expressed on the left and right sides of the embryo. Currently, we are studying the tight junction protein, Claudin-1. Tight junctions are critical for maintaining cell polarity and determining how cell layers interact since they regulate the paracellular transport of small molecules between cell layers. We showed that overexpression of Claudin-1 on the right side of the embryo randomizes the direction of heart looping, the first gross morphological sign of left-right asymmetry. We are now investigating the role of endogenous Claudin-1 and its interactions with other proteins at the tight junction cytoplasmic plaque in this process. In addition to Claudin-1, several other interesting molecules were identified in our screen and these will be the focus of future experiments. Characterizing the molecules that regulate the function of Pitx2c and those associated with Claudin-1 function will provide missing links in the left-right patterning program and open up new frontiers in our understanding of left-right axis formation and the development of asymmetry.

We are also exploring other functions of Claudin-1 and other members of the claudin family of tight junction proteins during embryogenesis. For example, Claudin-1 expression is dramatically downregulated in the cells that leave the epiblast to ingress through the primitive streak during gastrulation and during neural tube closure; defects in these processes lead to early pregnancy loss and serious developmental defects such as spina bifida. In addition, downregulation of Claudin-1 expression in tumour cells is correlated with increased metastasis and poorer survival rates. Thus, understanding how these molecules function in normal development is likely to contribute to a better idea of the pathophysiologies involved during abnormal development and disease.

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